[814-49-3] · C4H10ClO3P · Diethyl Phosphorochloridate · (MW 172.55)
(highly electrophilic phosphorylating reagent easily installed on anionic carbon,2 oxygen,3 nitrogen,4 and sulfur;5 ketones are converted to enol phosphates which can be reduced to alkenes6 or alkanes,7 or coupled with organometallic reagents to form substituted alkenes;8 enol phosphates can be tranformed into b-keto phosphonates,9 useful for Horner-Emmons homologation, or into terminal alkynes;10 used to convert carboxylic acids to other carboxylic derivatives11)
Alternate Name: diethyl chlorophosphate.
Physical Data: bp 60 °C/2 mmHg; d 1.194 g cm-3.
Handling, Storage, and Precautions: highly toxic, corrosive. Use in a fume hood.
Diethyl phosphorochloridate is highly electrophilic and can be cleanly reacted at an anionic center provided that prior metalation is regio- and chemoselective. For example, phenols,12 thiophenols,5 and anilines4 can be phosphorylated under basic conditions (eq 1). The phosphorylated compound can be isolated, or treated further with bases, resulting in orthometalation followed by a facile 1,3-phosphorus migration from the heteroatom to carbon. If carbon phosphorylation is desired, simply treating thiophenol with 2 equiv of n-Butyllithium followed by diethyl phosphorochloridate gave a moderate yield (58%).5
Synthetic preparation of oligonucleotides in a cost-efficient manner can be complicated by low chemoselectivity during phosphorylation, suggesting the need for prior nitrogen protection. It has been determined that despite the higher acidity of guanosine and thymidine over a hydroxy, addition of 1 equiv of the phosphorylating agent provided only the phosphates (eq 2).3 Adenosine and cytidine bases were compatible as well.
Phosphorylation of substituted 1,4-dihydropyridine dianions occurred selectively (eq 3).2b Other reports documented selective phosphorylation at C-5 of thiophenes2a and the ortho position of various substituted benzenes.13 It has been noted that certain heterocycles demonstrated alternative pathways, such as nucleophilic attack at carbon rather than phosphorus (eq 4).14
Trapping of ester, lactone, or ketone enolates results in rapid O-phosphorylation, thus providing the enol phosphate (eq 5).9 Further treatment with base resulted in facile rearrangement to the b-ketophosphonate (eq 5).15 However, regioisomeric b-ketophosphonates can often be observed from a regiochemically pure enol phosphate (eq 6).9a Since the classical Arbuzov reaction is limited to primary alkyl iodides (competing Perkov reaction is known with secondary halides), an alternative method was sought. Installation of an alkene blocking group sufficed (eq 7).9a Dienol phosphates have also been prepared and the authors note that Lithium 2,2,6,6-Tetramethylpiperidide was the preferred base for regiochemical control.16
b-Ketophosphonates are valuable intermediates in the realm of Horner-Emmons alkenation methodology. Acyclic variants are difficult to obtain from enol phosphates due to competing alkyne and allene formation. One solution utilized the dianion derived from a-bromo ketones and trapping with diethyl phosphorochloridate;17 however, only moderate yields of b-keto phosphonates were reported. The most efficient procedure utilizes the anion derived from dialkyl methylphosphonate, addition to an aldehyde, followed by oxidation (eq 8).18
Diethyl phosphorochloridate is useful for activation of carboxylic acids toward nucleophilic attack. Subsequent treatment of the phosphate ester with thallium sulfides produced thiol esters.19 Variations11 on this theme included prior formation of a heterocyclic phosphonate followed by treatment with alcohols, amines, or thiols, thus providing a racemization-free method to prepare esters, amides, and thiol esters, respectively (eq 9).11b
Amines can be readily transformed to an alcohol surrogate (eq 10)20 and phenols to anilines.21
Excision of oxygen from a molecule is often encountered in a synthetic sequence. Phenols are readily deoxygenated by formation of the phosphate followed by reduction under dissolving metal conditions.22 It has been noted that the Birch conditions result in low yields, whereas an alternative method utilizing activated Titanium metal is superior (eq 11).23 Under this protocol, enol phosphates are efficiently reduced as well.6b Conversion of an enone to a regiochemically defined alkene was accomplished via 1,4-reduction, enolate trapping, and reduction of the trapped enol phosphate (eq 12).6a Enol phosphates can be fully reduced to alkanes by hydrogenation of palladium catalysts7 or converted to vinyl iodides when treated with Iodotrimethylsilane.24
Enol phosphates are smoothly transformed into substituted alkenes when treated with organometallic reagents. If the enol phosphate was derived from a b-keto ester, cuprate reagents are generally reactive enough to encourage conjugate addition-phosphate elimination (eq 13).25 In the event that this coupling fails, the combination of Pd0 and Trimethylaluminum results in regio- and stereospecific methylation.8b Substrates lacking an ester moiety on the enol phosphate can be alkylated with Grignard reagents under nickel catalysis (eq 14).8a
One of the most useful applications of b-keto phosphonates is the Horner-Emmons alkenation procedure (eq 15).18 Variations of this theme have employed b-imino26 and b-sulfonyl phosphates.27
Alkynes are available from methyl ketones10 by elimination of the enol phosphate (eq 16).28 When the ketone contains a-branching, lithium tetramethylpiperidide has been recommended to circumvent allene formation.
Allylic phosphates have found applications in p-allyl palladium chemistry. It has been demonstrated that allylic phosphates undergo oxidative addition more readily than the corresponding acetate, such that chemoselectivity could be achieved when these functionalities were present in the same molecule (eq 17).29 Finally, b-keto phosphonates were coupled with epoxides to provide useful yields of spirocyclopropanes (eq 18).30
Jonathan R. Young
University of Wisconsin, Madison, WI, USA